Introduction

Uses for Tipranavir

Treatment of HIV Infection

Treatment of HIV-1 infection.1 Must be used in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir) and other antiretroviral agents.1

Used in patients who are antiretroviral-experienced and infected with HIV-1 resistant to multiple HIV PIs.1

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Not recommended in antiretroviral-naive individuals because of inferior virologic efficacy.1200

Risks versus benefits not established in pediatric patients <2 years of age.1

Consider the following factors when initiating ritonavir-boosted tipranavir: Use with other active antiretrovirals is associated with greater likelihood of treatment response; genotypic or phenotypic viral resistance testing and/or treatment history should guide therapy; number of baseline primary PI mutations affects virologic response to the drug; caution advised in patients at increased risk of hepatotoxicity or bleeding or in patients receiving certain drugs concomitantly.1 (See Cautions and see Interactions.)

Tipranavir Dosage and Administration

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).1200 Do not use without low-dose ritonavir.1200

Concomitant use with potent CYP3A inducers (e.g., rifampin, St. John’s wort [Hypericum perforatum]) when such use may result in decreased plasma concentrations of tipranavir and possible loss of virologic response.1

Evaluate hepatic function prior to and frequently during treatment.1 Patients with coexisting HBV or HCV infection or elevated serum transaminases prior to therapy may be at increased risk for hepatotoxicity, including further transaminase increases or hepatic decompensation.1

Discontinue if signs or symptoms of hepatitis develop, if asymptomatic increases in serum AST or ALT of >10 times the ULN occur, or if asymptomatic increases in AST or ALT of 5–10 times the ULN and increases in total bilirubin of >2.5 times the ULN develop.1

Intracranial Hemorrhage

Intracranial hemorrhage (including some fatalities) reported.19 Other medical conditions or concomitant therapy may have caused or contributed to these events.19

Ritonavir-boosted tipranavir therapy not associated with abnormal coagulation parameters; abnormal coagulation parameters have not preceded intracranial hemorrhage.19 Change in coagulation parameters (e.g., increased PT, increased aPTT, decreased vitamin K dependent factors) observed in rats given tipranavir; effects on these parameters increased in rats given concomitant vitamin E in the form of d-alpha-tocopherol polyethylene glycol 1000 succinate; changes in coagulation parameters not observed in other species (i.e., dogs) given tipranavir.1

Manufacturer states that routine monitoring of coagulation parameters not necessary.1

Interactions

Tipranavir must be used with low-dose ritonavir (ritonavir-boosted tipranavir).1 Failure to administer with recommended low-dose ritonavir will result in subtherapeutic tipranavir concentrations and inadequate antiviral response.1 Consider the usual cautions, precautions, and contraindications associated with ritonavir.1

Effects on Platelets and Coagulation

Caution advised in patients who may be at risk for increased bleeding from trauma, surgery, or other medical conditions; those receiving concomitant drugs known to increase the risk of bleeding (i.e., anticoagulants, antiplatelet agents); and those receiving high-dose vitamin E.1

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1

Hepatic Impairment

Risk for further elevations in hepatic enzyme concentrations or severe liver disease in patients with chronic HBV or HCV or increased AST or ALT concentrations prior to therapy.1 (See Hepatic Effects under Cautions.)

Rifabutin: Reduce rifabutin dosage to 150 mg every other day or 3 times weekly (further reduction may be needed); increase monitoring for adverse effects;1200 monitor for antimycobacterial response and consider therapeutic drug monitoring200

Concomitant use with oral midazolam or triazolam contraindicated;1 some experts state a single parenteral dose of midazolam can be used with caution in a monitored situation for procedural sedation200

Boceprevir

Concomitant use with ritonavir-boosted tipranavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) decreases concentrations and AUCs of boceprevir and the HIV PIs17185 and may reduce efficacy of HCV and HIV treatment1718

Concomitant use with low-dose ritonavir alone results in decreased boceprevir concentrations and AUC185

In patients already receiving ritonavir-boosted tipranavir for ≥10 days, initiate bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1

In patients already receiving bosentan, discontinue bosentan for at least 36 hours prior to initiating ritonavir-boosted tipranavir; after ≥10 days of ritonavir-boosted tipranavir, resume bosentan using dosage of 62.5 mg once daily or every other day based on individual tolerability1

Buprenorphine, buprenorphine/naloxone

Decreased tipranavir concentrations;1200 no effect on clinical efficacy of buprenorphine/naloxone1

Patients with renal or hepatic impairment: Avoid concomitant use of colchicine and ritonavir-boosted tipranavir1

Colchicine for treatment of gout flares: In those receiving ritonavir-boosted tipranavir, use initial colchicine dose of 0.6 mg followed by 0.3 mg 1 hour later and repeat dose no earlier than 3 days later1

Colchicine for prophylaxis of gout flares: In those receiving ritonavir-boosted tipranavir, decrease colchicine dosage to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decrease dosage to 0.3 mg once every other day in those originally receiving 0.6 mg once daily1

Colchicine for treatment of familial Mediterranean fever (FMF): In those receiving ritonavir-boosted tipranavir, use maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily)1

Modification of usual dosage of clarithromycin or tipranavir not necessary in patients with normal renal function; reduce clarithromycin dosage by 50% if Clcr 30–60 mL/minute and reduce by 75% if Clcr <30 mL/minute1200

If treatment of uterine atony and excessive postpartum bleeding is indicated in a woman receiving tipranavir, use methylergonovine maleate (Methergine) only if alternative treatments cannot be used and if potential benefits outweigh risks; use methylergonovine at lowest dosage and shortest duration possible202

Manufacturer of tipranavir does not recommend increasing meperidine dosage or concomitant long-term use because of potential for increased normeperidine concentrations and possible analgesic and CNS-stimulating activity (e.g., seizures) 1

Tadalafil for treatment of PAH in patients who have been receiving ritonavir-boosted tipranavir for ≥1 week: Use initial tadalafil dosage of 20 mg once daily; if tolerated, may increase dosage to 40 mg once daily1

Ritonavir-boosted tipranavir in patients receiving tadalafil for PAH: Discontinue tadalafil for at least 24 hours prior to initiating ritonavir-boosted tipranavir; after ≥1 week of the antiretroviral agent, may resume tadalafil at dosage of 20 mg once daily and, if tolerated, may increase dosage to 40 mg once daily1

Tadalafil for treatment of benign prostatic hyperplasia: Do not exceed tadalafil dosage of 2.5 mg once daily200

Telaprevir

Concomitant use with low-dose ritonavir alone results in decreased telaprevir concentrations and AUC184

Concomitant use with ritonavir-boosted tipranavir not studied; concomitant use with other ritonavir-boosted PIs (ritonavir-boosted atazanavir, ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) decreases concentrations and AUC of telaprevir and decreases concentrations of some of the HIV PIs (darunavir, fosamprenavir)184

Concomitant use not recommended pending further accumulation of data200

Following >2 weeks of multiple oral doses given without regard to meals, peak plasma tipranavir concentrations attained approximately 3 hours after a dose.1

Steady state attained in most patients after 7–10 days.1 Steady-state trough concentrations are 70% lower than day 1, presumably due to intestinal p-glycoprotein induction.1

Food

Compared with administration in the fasting state, administration of tipranavir (as capsules or oral solution) and ritonavir (as capsules) with a meal (500–682 kcal, 23–25% calories from fat) does not have a clinically important effect on tipranavir peak plasma concentrations or AUC.1

Effect of food on administration of tipranavir (as capsules or oral solution) with ritonavir (as tablets) not evaluated.1

Stability

Storage

Oral

Capsules

2–8°C prior to opening bottle;1 after opening bottle, store at 25°C (may be exposed to 15–30°C) and use within 60 days.1

Oral Solution

25°C (may be exposed to 15–30°C);1 do not refrigerate or freeze.1 After opening bottle, use within 60 days.1

Actions and Spectrum

Tipranavir must be administered in conjunction with low-dose ritonavir (ritonavir-boosted tipranavir).1

Tipranavir is extensively metabolized by CYP3A; ritonavir is a potent inhibitor of CYP3A.1 Concomitant use of these drugs results in decreased metabolism and increased plasma concentrations of tipranavir.1

Active against HIV-11 Also has some activity against HIV type 2 (HIV-2) in vitro.13

Tipranavir inhibits replication of HIV-1 by interfering with HIV proteases.1

Tipranavir-resistant HIV-1, including strains with decreased susceptibility to other HIV PIs, has been reported.1

Advice to Patients

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1

Importance of using tipranavir with low-dose ritonavir; importance of using these 2 drugs in conjunction with other antiretrovirals.1

Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 Sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to AIDS and death.1

Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1200

Importance of reading patient information provided by the manufacturer.1

Importance of taking tipranavir at the same time as ritonavir.1 If tipranavir is taken with ritonavir capsules or oral solution, take the drugs with or without meals.1 If tipranavir is taken with ritonavir tablets, take the drugs with a meal.1

Importance of swallowing tipranavir capsules whole; capsules should not be chewed.1

If a dose is missed, take the dose as soon as it is remembered and take next dose at regularly scheduled time.1 If a dose is skipped, do not take a double dose to make up for the missed dose.1

Importance of patient informing their clinician if they are allergic to sulfonamides.1

Possibility of fatal or nonfatal intracranial hemorrhage.1 Importance of informing clinician of unusual or unexplained bleeding.1

Need for periodic clinical and laboratory monitoring, including liver function tests, prior to and during treatment.1 Importance of extra vigilance in patients with chronic HBV or HCV coinfection because of increased risk of hepatotoxicity.1

Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., vitamin E supplements) and herbal products (e.g., St. John’s wort), and any concomitant illnesses.1

Advise patients receiving selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual disturbances, priapism) and that any symptoms should be promptly reported to their clinician.1Ritonavir-boosted tipranavir should not be used concomitantly with sildenafil used for treatment of pulmonary arterial hypertension (PAH).1

Importance of women using a reliable nonhormonal (e.g., barrier) method of contraception because of the potential interaction with hormonal contraceptives.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise HIV-infected women not to breast-feed.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Tipranavir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

250 mg

Aptivus

Boehringer Ingelheim

Solution

100 mg/mL

Aptivus

Boehringer Ingelheim

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (April 18, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (August 11, 2011). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (July 31, 2012). Updates may be available at HHS AIDS Information (AIDSinfo) website.